title: 3D matched pairs: integrating ligand- and structure-based knowledge for ligand design and receptor annotation.
abstract: We describe an extension to the matched molecular pairs approach that merges pairwise activity differences with three-dimensional contextual information derived from X-ray crystal structures and binding pose predictions. The incorporation of 3D binding poses allows the direct comparison of structural changes to diverse chemotypes in particular binding pockets, facilitating the transfer of SAR from one series to another. Integrating matched pair data with the receptor structure can also highlight activity patterns within the binding site--for example, "hot spot" regions can be visualized where changes in the ligand structure are more likely to impact activity. The method is illustrated using P38α structural and activity data to generate novel hybrid ligands, identify SAR transfer networks, and annotate the receptor binding site.
authors.affiliation: Computer-Assisted Drug Design, Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA.
authors.forename: Shana L
authors.initials: SL
authors.lastname: Posy
authors.forename: Brian L
authors.initials: BL
authors.lastname: Claus
authors.forename: Matt E
authors.initials: ME
authors.lastname: Pokross
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Johnson
mesh_terms: D001665:Binding Sites; D062313:Databases, Pharmaceutical; D015195:Drug Design; D006801:Humans; D008024:Ligands; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D058977:Molecular Sequence Annotation; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D048308:Mitogen-Activated Protein Kinase 14